Thrombin is able to elicit many cellular responses (e.g. thrombotic, inflammatory, proliferative and atherosclerotic) that are mediated by proteolytic activation of a specific cell surface receptor known as the thrombin receptor (Vu et al. (1991) Cell 64: 1057-1068; Rasmussen et al. (1991) FEBS Lett 288: 123-128; Zhong et al. (1992) J. Biol. Chem. 267: 16975-16979; Bahou et al. (1993) J. Clin. Invest. 91: 1405-1413; McNamara et al. (1993) J. Clin. Invest. 91: 94-98; Glembotski (1993) J. Biol. Chem. 268: 20646-20652; and Park et al. (1994) Cardiovasc. Res. 28: 1263-1268. The thrombin receptor has seven transmembrane-spanning domains and belongs to a family of G-protein coupled receptors (Vu et al. (1991) Cell 64: 1057-1068 and Schwartz (1994) Current Opin. Biotechnol. 5: 434-444). The thrombin receptor is a specific tethered ligand receptor or protease activated receptor. Activation of the receptor occurs by thrombin cleavage of an extracellular N-terminal domain. The new N-terminus through intramolecular interaction activates the receptor (Vu et al. (1991) Cell 64: 1057-1068; Coughlin (1993) Thromb. Haemostas. 70: 184-187; Van Obberghen-Schilling and Pouyssegur (1993) Thromb. Haemostas. 70: 163-167; Brass et al. (1994) Ann. NY Acad. Sci. 714: 1-12). Synthetic thrombin receptor activating peptides comprising the 6-14 amino acids of the tethered ligand were found to activate platelets equally with thrombin itself and are considered to be full agonists (Vu et al. (1991) Cell 64: 1057-1068; Vassallo et al. (1992) J. Biol. Chem. 267: 6081-6085; Coller et al. (1992) Biochemistry 31: 11713-11722; Chao et al. (1992) Biochemistry 31 6175-6178; Rasmussen et al. (1993) J. Biol. Chem. 268: 14322-14328). The first five amino acids (SFLLR) are required for activation of the platelet thrombin receptor (Scarborough et al. (1992) J. Biol. Chem. 267: 13146-13149;Hui et al. (1992) Biochem. Biophys. Res. Commun. 184: 790-796). Structure activity studies, NMR experiments and molecular modeling have determined the specific requirements for each amino acid in SFLLR (Matsoukas et al. (1997) J. Prot. Chem. 16: 113-131; Natarajan et al. (1995) Int. J. Pept. Protein Res. 45: 145-151).
Antagonists of the thrombin receptor are medicinally useful agents for blocking the unwanted effects of thrombin on cells.
Compounds of the invention are useful for inhibiting the aggregation of blood platelets. The above-mentioned compounds, which are thrombin receptor antagonists, can be used in a method of acting upon a thrombin receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of active drug is another feature of this invention.
The present invention includes compounds having the structure 
and pharmaceutically acceptable salts thereof, wherein
R1 is hydrogen or C1-10 alkyl;
R2 is
C1-10 alkyl,
C3-8 cycloalkyl,
CH(CH3)CH2OCH3,
CH(CH3)CH2F,
CH(CH3)CH2SCH3,
A is hydrogen or 
A1, A2, A3, and A4 are independently selected from
hydrogen,
halogen,
nitro,
CN,
R10,
OR10,
NR10R11;
m is 0, 1, 2, 3, 4, or 5;
B is
hydrogen,
R12,
C3-8 cycloalkyl,
CH(CH3)CH2OCH3,
CH(CH3)CH2F,
CH(CH3)CH2SCH3;
R6 is
R13,
Ar2,
NH(Ar2),
C3-8 cycloalkyl,
CH2Ph,
C(CH3)2NC(O)OC(CH3)3,
C(NH2)(CH3)2, or
OC(CH3)3,
X is
OH,
OR4,
OC(O)R4,
OC(O)Ar1,
NR4Ar1,
SR4,
S(O)R4,
SO2R4;
R4, R9, R10, R11, R12, and R13 are independently selected from hydrogen or C1-10 alkyl; and
Ar, Ar1 and Ar2 are independently selected from the group consisting of
i) aryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C1-10 alkyl,
CH2NHC(O)NH2,
halogen,
CN,
amino C1-10 alkyl,
CF3, or
S(O)nR3, wherein R3 is hydrogen or C1-10 alkyl, or
ii) heteroaryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C1-10 alkyl,
halogen,
CN,
amino C1-10 alkyl,
CF3, or
S(O)nR3, wherein R3 is hydrogen or C1-10 alkyl.
In a class of compounds of the invention, and pharmaceutically acceptable salts thereof,
R4 is CH3, C(CH3)3, or CH2CH3;
R10 is CH3;
R13 is CH(CH3)2, CH2CH3, or CH3;
Ar2 is
phenyl, unsubstituted, monosubstituted or independently disubstituted with F, S(O)2NH2, Cl, CH2NHC(O)NH2, or CH3, 
xe2x80x83unsubstituted, monosubstituted or independently disubstituted with F, 
In a group of the class of compounds, and pharmaceutically acceptable salts thereof,
Ar is 
X is
OH,
OCH3,
OC(O)C(CH3)3,
OC(O)C3, 
OCH2CH3;
R2 is
CH(CH3)2,
C(CH3)3,
CH2CH3, 
CH2CH2CH3,
CH(CH3)2CH2CH3,
CH(CH3)CH2CH3,
CH(CH2CH3)2,
CH(CH3)CH2OCH3,
CH(CH3)CH2CH2CH3,
CH(CH3)CH2F, or
CH(CH3)CH2SCH3;
A1 is
hydrogen,
Cl,
F,
CH3, or
CN;
A2 is
hydrogen,
F, or
OCH3;
A3 and A4 are hydrogen;
m is 0, 1, or 2;
B is hydrogen;
R6 is 
CH3,
C(CH3)3,
CH2Ph,
Ph,
C(CH3)2NC(O)OC(CH3)3,
C(NH2)(CH3)2, 
Examples of the group of compounds include 
and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d means branched or straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, xe2x80x9cC1-10xe2x80x9d denotes alkyl having 1 to 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like.
The term xe2x80x9calkenylxe2x80x9d means hydrocarbon chains of either a straight of branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur at an stable point along the chain, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like.
The term, xe2x80x9calkynylxe2x80x9d means hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, e.g., ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, radicals and the like.
The terms xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure. Such xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, may alternatively and equivalently be denoted herein as xe2x80x9c-(alkyl)-xe2x80x9d, xe2x80x9c-(alkenyl)-xe2x80x9d and xe2x80x9c-(phenyl)-xe2x80x9d, and the like.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, iodine and bromine.
The term xe2x80x9coxyxe2x80x9d means an oxygen (O) atom.
The term xe2x80x9cthioxe2x80x9d means a sulfur (S) atom.
The term xe2x80x9carylxe2x80x9d means a partially saturated or fully saturated 6-14 membered ring system such as for example, phenyl, naphthyl or anthracyl. The term xe2x80x9cPhxe2x80x9d, which appears in certain chemical formulas in the specification and claims, represents phenyl.
The term xe2x80x9ccycloalkylxe2x80x9d means saturated ring groups, including mono-, bi-, or poly-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, cycloheptyl, cyclooctyl, adamantyl, and the like.
The term xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d means a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or fully unsaturated, which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of heterocyclic rings include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9cheteroarylxe2x80x9d means an unsaturated heterocyclic group, preferably 5 or 6-membered monocyclic ring systems or 8-10 membered fused bicyclic groups, having heteroatoms selected from the group consisting of N, O, and S, for example, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, a methylene substituted with ethylcarbonylamino is equivalent to 
Compounds of the present invention may be chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention. Thus, the term xe2x80x9cactive drugxe2x80x9d includes a compound of the invention and its salts, racemic mixtures or separated enantiomers, hydrates or anhydrous forms, polymorphs, and pharmaceutically acceptable salts.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.
Prodrugs, such as ester derivatives of active drug are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician. The term xe2x80x9canti-coagulantxe2x80x9d shall include heparin, and warfarin. The term xe2x80x9cthrombolytic agentxe2x80x9d shall include agents such as streptokinase and tissue plasminogen activator. The term xe2x80x9cplatelet anti-aggregation agentxe2x80x9d shall include agents such as aspirin and dipyridamole.
In the schemes and examples below, various reagent symbols have the following meanings:
Active drug can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, it may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of active drug can be employed as an anti-aggregation agent.
Active drug may be administered to patients where prevention of thrombosis by inhibiting binding of thrombin to the thrombin receptor is desired. It is useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Active drug may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Other applications of active drug include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures. It may also be used to prevent myocardial infarction.
The dosage regimen utilizing active drug is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Oral dosages of active drug when used for the indicated effects, will range between about 0.005 mg per kg of body weight per day (mg/kg/day) to about 50 mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 0.005-10 mg/kg/day. For example, a typical 90 kg patient would receive oral dosages ranging between about 0.45 mg/day and about 4.5 g/day, most preferably between about 1.0 mg/day and 1.0 g/day. Suitable pharmaceutical oral compositions such as tablets or capsules may contain 1-500 mg, for example, 1 mg, 10 mg, 100 mg, 200 mg and 500 mg. Intravenously, the most preferred doses will range from about 0.5 to about 5 mg/kg/minute during a constant rate infusion. Active drug may be administered in one or divided doses of two, three, or four times daily. Furthermore, active drug can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
In the methods of the present invention, the active drug can form the active ingredient, and is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
The active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
Active drug can also be co-administered with the usual doses of suitable anticoagulation agents, such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug), to achieve beneficial effects in the treatment of various vascular pathologies. Such co-administration also includes administration if the active drug with doses of anticoagulant agents or thrombolyric agents less than the usual doses of those agents.
Compounds of the invention were prepared according to the following general schemes, including the specific procedures described in the following examples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. 
For example, in the above scheme, Rxe2x80x2 can be isopropyl or the like, n can be 1, and Rxe2x80x3 can be 5 (1H-benzimidazole)or the like. 
For example, in the above scheme, X and Xxe2x80x2 can independently be hydrogen or halogen. 
For example, in the above scheme, Rxe2x80x2 can be cyclobutyl or the like and Rxe2x80x3 can be chloro, e.g. meta chloro, or the like. 
For example, in the above scheme, Rxe2x80x2 can be isopropyl or the like, Rxe2x80x3 can be tert butyl or the like, and Rxe2x80x2xe2x80x3 can be acetyl or the like. 
For example, in the above scheme, X and Xxe2x80x2 can independently be hydrogen or halogen, and R6 is NH(Ar2).
Compounds of the invention may also be prepared according to general procedures outlined in S. Hutchins et al. Tetrahedron Lett., 1995, 36, 2583-2586 and S. Hutchins et al. Tetrahedron Lett., 1994, 35, 4055-4058.